One approach to the cure of advanced cancer is by the use of more intensive chemotherapy. To avoid severe or life-threatening bone marrow toxicity accompanying this treatment, stem cell support in association with high-dose chemotherapy regimens is currently being evaluated for many tumors. However, even in this circumstance, the patient's stem cells and marrow capacity for regenerating normal hematopoiesis are often eventually severely limited. The goal of this proposal is to establish a chemotherapy-resistant population of bone marrow cells which can result in the use of higher doses of chemotherapy with less toxicity. Normal bone marrow cells express low levels of the human multiple drug resistance (MDR) gene, and thus, are susceptible to killing by classes of drugs that require the action of the MDR gene transmembrane protein, p-glycoprotein, for their export from cells; these drugs include the anthracyclines, vinca alkaloids, podophyllins and taxanes, all commonly used to treat cancer. We have already shown that we have a safe retroviral vector that can transfer and express the human MDR gene in CD34+ cells, and provide paclitaxel resistance to these cells. However, in a Phase 1 clinical trial, we have seen only low level MDR transduction in patients. We now propose to find more effective methods to transduce human hematopoietic stem cells (HSC) with the human MDR gene to establish a drug-resistant bone marrow in vivo. These studies could lead to conditions for permitting higher doses of chemotherapy to be administered to advanced cancer patients with less hematologic toxicity, longer remissions or potential cure of these patients.